Abstract

BACKGROUND:

A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.

METHODS:

We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study).

RESULTS:

At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.

CONCLUSIONS:

This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

Panel A shows the mean nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) at baseline and day 14 during part 1 of the study in each of the four study groups. The I bars indicate the ranges, and the dashed line indicates no response. Panel B shows the mean nasal potential difference at baseline, day 14, and day 28 during part 2 of the study in each study group. The I bars indicate the ranges, and the dashed line indicates no response. Panel C shows the change in the nasal potential difference from baseline to day 14 in individual subjects (indicated by symbols) in each study group and the least-squares means (indicated by solid lines) from the mixed model in part 1 of the study. The dashed line indicates no change. Panel D shows the change in the nasal potential difference from baseline to day 14 or day 28 in individual subjects (indicated by symbols) in each study group and the medians (indicated by solid lines) in part 2 of the study. The dashed line indicates no change. P values are for within-subject comparisons.

Panel A shows the mean sweat chloride concentration at baseline and days 7 and 14 during part 1 of the study for each study group. The I bars indicate the ranges. Panel B shows the mean sweat chloride concentration at baseline and days 3, 14, 21, and 28 during part 2 of the study for each study group. The I bars indicate the ranges. The dashed lines in Panels A and B indicate the lower limit of abnormal sweat chloride concentrations. Panel C shows the change in the sweat chloride concentration from baseline to day 14 in individual subjects (denoted by symbols) in each study group and the least-squares means (indicated by solid lines) from the mixed model in part 1 of the study. P<0.001 for all comparisons (within-subject and vs. placebo). The dashed line indicates no change. Panel D shows the change in the sweat chloride concentration from baseline to day 14 or day 28 in individual subjects (symbols) in each study group and the medians (indicated by solid lines) in part 2 of the study. At day 14, in the VX-770 150-mg group, P = 0.02 for within-subject comparisons and P = 0.03 versus placebo. In the VX-770 250-mg group, P = 0.02 for within-subject comparisons and P = 0.05 versus placebo. At day 28, in the VX-770 150-mg group, P = 0.008 for within-subject comparisons and P = 0.02 versus placebo. In the VX-770 250-mg group, P = 0.02 for within-subject comparisons and P = 0.03 versus placebo. The dashed line indicates no change.

Panel A shows the mean change from baseline to day 14 in the forced expiratory volume in 1 second (FEV1) during part 1 of the study in each study group. In the VX-770 150-mg group, P = 0.006 for within-subject comparisons and P = 0.04 versus placebo. In the VX-770 75-mg group, P = 0.003 for within-subject comparisons and P = 0.05 versus placebo. The I bars indicate the ranges. Panel B shows the median FEV1 change from baseline during part 2 of the study in each study group. In the VX-770 250-mg group, P = 0.02 for within-subject comparisons for all time points shown except for day 28, when P = 0.03 for within-subject comparisons. In the VX-770 150-mg group, P = 0.05 for within-subject comparisons at day 3 and P = 0.008 for within-subject comparisons at days 14, 21, and 28. The I bars indicate the ranges. Panel C shows the relative change from baseline in the percentage of predicted FEV1 from baseline to day 14 in individual subjects (indicated by symbols) in each study group and the least-squares means (indicated by solid lines) from the mixed model in part 1 of the study. In the VX-770 75-mg group, P = 0.002 for within-subject comparisons, and in the VX-770 150-mg group, P = 0.008 for within-subject comparisons. Panel D shows the relative change in the percentage of predicted FEV1 from baseline to day 14 and day 28 in individual subjects (indicated by symbols) in each study group and the medians (indicated by solid lines) in part 2 of the study. At day 14, in the VX-770 150-mg group, P = 0.008 for within-subject comparisons. In the VX-770 250-mg group, P = 0.02 for within-subject comparisons. At day 28, in the VX-770 150-mg group, P = 0.008 for within-subject comparisons. In the VX-770 250-mg group, P = 0.03 for within-subject comparisons. In all four panels, the dashed lines indicate no change from baseline.